Abstract: Mosquito-borne flaviviruses cause disease worldwide, with members such as dengue virus (DENV), Zika virus (ZIKV) and west nile virus (WNV) infecting more than 100 million individuals annually. The availability of small molecule antivirals that reduce flavivirus infection therefore could have an immediate and substantial impact on public health programs that seek to improve outcomes for populations infected with WNV, DENV, and ZIKV. Recently, genome-wide screening using either insertional mutagenesis or CRISPR-Cas9 knockout approaches have identified subunits of the oligosaccharyltransferase (OST), specifically STT3A and STT3B, as essential for the flavivirus life cycle. Drug discovery efforts using a novel bioluminescent reporter that detects inhibition of OST function have also had recent success with the identification of novel small molecules that target the OST [13]. This class of inhibitors directly engage with the STT3A and STT3B subunits and therefore have the potential to be antiviral agents for the treatment of flavivirus infection. The proposed research seeks to structurally optimize the potency and solubility of this drug-like small molecule series in order to advance this therapeutic strategy for preclinical testing.